Amyloid Pioneer: It's Not Over Yet

Author of the "amyloid cascade hypothesis" maintains positive outlook

Although several researchers had previously published findings on beta-amyloid's potential pathophysiological role in Alzheimer's disease, a two-page perspective published in Science in 1992 by John Hardy, PhD, of University College London, and Gerald Higgins, PhD, of the National Institute on Aging, is often credited as the genesis of the amyloid cascade hypothesis.

It provided a potential genetic explanation for amyloid accumulation in the brain as a cause of Alzheimer's: patients with Down syndrome often developed Alzheimer's in their 30s or 40s, and the key mutation in Down's is trisomy of chromosome 21, which contains the amyloid precursor protein (APP) gene.

Hardy answered questions about the paper and the current state of the amyloid cascade hypothesis via an email exchange with MedPage Today.

MedPage Today: How did you arrive at your original hypothesis?

Hardy: In 1992, there were many hypotheses about Alzheimer's disease. I felt genetics was a way to referee between these hypotheses. So when we found amyloid mutations, I felt this said that those who had said amyloid was the start, were correct. These were Glenner and Masters and Beyreuther. I felt I was the referee, not the originator, and that our group finding amyloid mutations settled the matter.

MPT: What was the response to your paper after it was published in Science in 1992?

Hardy: It was quiet initially. It only took a weekend to write. I am always surprised what a long-term "hit" this article and the one I wrote with David Allsop at the same time have been.

MPT: What were your next steps in testing the hypothesis?

Hardy: Finding and understanding presenilin mutations and showing that these influenced amyloid. Peter Hyslop and Steve Younkin were important here. And finding tau mutations in Pick's disease and showing these were downstream of amyloid in both mice and humans. Mike Hutton and Jada Lewis were key here.

MPT: Did you get involved in anti-amyloid drug development?

Hardy: No, but see this Annals of Neurology paper by Karran and Hardy for a discussion. Editor's Note: The paper suggests that recent evidence of efficacy in early-stage disease and pending results from several large prevention trials in both familial and sporadic disease "provide sustenance to those drug developers and scientists who believe that the amyloid hypothesis has yet to be tested and that ultimately the field will refute the null hypothesis to provide effective therapies for this devastating disease."

MPT: Where do you think the amyloid hypothesis stands today, and what is its place in research going forward?

Hardy: It's definitely true in amyloid-mutation families, Down syndrome, and presenilin-mutation families. It is likely to be true, but not [yet] proven, in other cases.

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